Crystal Structure of an LSD-Bound Human Serotonin Receptor

Es wird eine rationelle Synthese fur das Bufotenin und andere ω-N-substituierte 5-Oxy-tryptamine angegeben. Folgende neue Verbindungen aus der Reihe der Oxy-tryptamine werden beschrieben: 5-Oxy-ω-N-methyl-tryptamin, 5-Oxy-ω-N-athyl-tryptamin, 5-Oxy-ω-N, N-diathyl-tryptamin, 5-Oxy-ω-N-β-aminoathyl-tryptamin, N-[β-(5-Oxy-indolyl-(3))-athyl]-piperidin, sowie zwei Stellungsisomere des Serotonins, das 4-Oxy-tryptamin und das 6-Oxy-tryptamin.

Eine neue Synthese von Bufotenin und verwandten Oxy‐tryptaminen. 40. Mitteilung über Mutterkornalkaloide

Ergot alkaloids is a group of natural biologically active compounds belonging, according to the general alkaloid classification, to the class of indole derivatives. Ergot alkaloids are found in largest amounts in the fungal species of Claviceps genus, the most widely occurring source of these substances being purple ergot (Claviceps purpurea Fr. Tul.) [1 – 6]. Another well-known fungal species producing alkaloids of the clavine series is Claviceps paspali [1, 3, 4, 6 – 8]. Ergot alkaloids are rarely encountered in higher plants; examples are offered by the Ipomoea genus of the Convolvulaceae family occurring in Central America [4, 9, 10]. The life cycle of ergot consists of three sequential stages, including the (i) conidial stage of sphacelia, (ii) sclerotium (resting stage), and (iii) sephalated stroma with perithecium. The alkaloids are obtained from ergot sclerotium called “spurred rye” (Secale cornutum) [4 – 6, 11]. The ergot sclerotium contains up to 30 – 40% of fatty oils and up to 2% of alkaloids. The other components of sclerotium are free amino acids, ergosterin, choline, acetylcholine, betaine, ergothionine, uracil, guanidine, free aromatic and heterocyclic amines (tyramine, histamine, agmatine), and alkylamines (the natural representatives of which were originally found in ergot). The outer shell of sclerotium contains acid pigments belonging to anthraquinolinic acid derivatives, including orange-red (endocrocin, clavorubin) and light-yellow (ergochromes, ergochrysins). These pigments impart to the sclerotium shell the characteristic grayish-brown-violet color [6, 12 – 15]. Also encountered are the albino ergot strains incapable of producing pigments [16]. Investigation of the wild-growing Cl. purpurea species revealed the existence of numerous geographic types differing in both qualitative and quantitative composition of alkaloids. To the present, ergot strains were specially selected that are capable of producing predominantly a single alkaloid or a certain group of alkaloids: ergotamine, ergotoxin, ergocristine, etc. [3, 4, 6, 16 – 27]. Owing to a high biological activity and broad spectrum of pharmacological effects, ergot alkaloids are of considerable importance for medicine. These compounds are now obtained both by methods of artificial parasitic cultivation on rye [11, 14, 19 – 22, 25 – 30] and by saprophytic growth techniques [31 – 35]. The most widely known pharmacological effect of ergot alkaloids is the ability to induce uterine contraction. Ergot extracts were officially used for the first time in gynecology. The best known drugs of this type are ergotamine and ergometrine. As the chemical structure and pharmacological properties of ergot alkaloids were studied, the scope of their application considerably expanded. Ergot alkaloids exhibit a complicated action upon the organism, which accounts for a variety of possible therapeutic applications. Dihydroxy derivatives of ergotoxin alkaloids produce -adrenoblocking and “venotonic” action. These compounds are administered in cases of hypertension, cerebral vasospasms, peripheral circulation disorders, etc. [36 – 39]. Many ergot alkaloids produce a more or less pronounced dopaminergic effect. Specific dopamine agonists are 2-Brand 2-Br-ergocryptines, which influence the secretion of hypophyseal anterior hormones and produce a hypotensive action upon the CNS, sympathetic nerve endings, and smooth vascular muscles. The drug abergin (Russia) [36, 37] or parlodel (bromergon, bromocriptine mesylate) are used for the treatment of a wide spectrum of disorders, including galactorrhea, acromegalia, mastites, prolactinomas, amenorrhea, and infertility and for the suppression of lactation, Cushing’s disease, some hormonal tumors, etc. [1, 36 – 44].

The Chemistry of Peptide Ergot Alkaloids. Part 1. Classification and Chemistry of Ergot Peptides

Ergot has a remarkable history. Man first made contact with it as a violent poison when the consumption of rye infected with ergot led to the severe symptoms of ergotism. How this poison came to be used as a remedy is not quite clear. Formal medicine was opposed to the therapeutic use of ergot, but midwives long ago availed themselves of it for promoting childbirth and for arresting postpartum hemorrhage. Starting with this knowledge, the American physician Stearns‘ published in 1808 the first scientific paper recommending ergot for these purposes. His publication aroused interest in the scientific study of ergot and its therapeutic applications, not only in America but also in Europe. Advances in chemistry and, especially, improvements in preparative techniques, have made it possible to isolate a series of substances, some of which occur elsewhere in nature, the biogenic amines for example, while others, the characteristic alkaloids, are specific to ergot. Until 1925, the use of these alkaloids in medicine was restricted to the fields of obstetrics and gynecology. A second phase in the history of ergot began when we showed that the sympathicolytic properties of ergot, first described by Dale,2 had a therapeutic application. Following the clinical trials that we instigated, first ergotarnine alone and then the combination of ergotamine with belladonna alkaloids and phenobarbital were added to the therapeutic arma~entarium.~ Special interest was aroused by the use of ergotamine in migraine.4 The most recent and third phase in the history of ergot followed our discovery of the central actions of ergotamine. In 1923, the inhibition of the depressor reflexes was de~cribed;~ in 1934, we were able to show that ergotamine potentiates the action of phenobarbital without itself possessing a hypnotic action; and in 1944, we demonstrated the central action of the hydrogenated alkaloids of the ergotoxine group.6a, 6b The increased interest that followed this extension of the field of therapeutic indications also stimulated interest in the chemistry of ergot. Stoll and his associates’ succeeded in carrying out a partial synthesis of ergonovine (ergometrine) and, as far back as 1938,s a rather closely related derivative, the diethylamide of lysergic acid (LSD), was synthesized by these workers. Like ergonovine, this compound proved to have a pronounced action on the uterus and the vagina when tested in the rabbit. The remarkable psychic effects of LSD were discovered by chance in 1943 when A. Hofmann, a chemist engaged in the preparation of this compound, inadvertently ingested a minute quantity of it. In experiments on ourselves, my collaborators and I were able to confirm Hofmann’s observation, and W. A. Stollg undertook the first systematic psychiatric investigation of this “phantasticum,” as he called it, My object here is to furnish an account of the pharmacological characteristics of LSD and some of its related compounds.

Lysergic acid diethylamide and related substances.

This chapter will summarize structure–activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT2A receptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT2A receptor is the principal mechanism of action for psychedelics, compounds with 5-HT2A agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT2A receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.

Chemistry and Structure–Activity Relationships of Psychedelics

Es werden Darstellung und Eigenschaften einer grossern Anzahl saureamidartiger Derivate der Lysergsaure, Isolysergsaure, Dihydro-lysergsaure(I) und Dihydro-isolysergsaure(I) mit primaren und sekundaren Aminen beschrieben.

A. Hofmann

Papers

Amide der stereoisomeren Lysergsäuren und Dihydro‐lysergsäuren. 38. Mitteilung über Mutterkornalkaloide